Control of anti-apoptotic and antioxidant pathways in neural cells

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Abstract

Oxidative stress is a feature of many chronic neurodegenerative diseases as well as a
contributing factor in acute disorders including stroke. Fork head class of
transcription factors (Foxos) play a key role in promoting oxidative stress-induced
apoptosis in neurons through the upregulation of a number of pro-apoptotic genes.
Here I demonstrate that synaptic NMDA receptor activity not only promotes Foxos
nuclear exclusion but also suppresses the expression of Foxo1 in a PI3K-dependent
fashion. I also found that Foxo1 is in fact, a Foxo target gene and that it is subject to
a feed-forward inhibition by synaptic activity, which is thought to result in longerterm
suppression of Foxo downstream gene expression than previously thought. The
nuclear factor (erythroid 2-related) factor 2 (Nrf2) is another transcription factor
involved in oxidative stress and the key regulator of many genes, whose products
form important intrinsic antioxidant systems. In the CNS, artificial activation of Nrf2
in astrocytes has been shown to protect nearby neurons from oxidative insults.
However, the extent to which Nrf2 in astrocytes could respond to endogenous signals
such as mild oxidative stress is less clear. The data presented herein, demonstrate for
the first time that endogenous Nrf2 could be activated by mild oxidative stress and
that this activation is restricted to astrocytes. Contrary to the established dogma, I
found that mild oxidative stress induces the astrocytic Nrf2 pathway in a manner
distinct from the classical Keap1 antagonism employed by prototypical Nrf2
inducers. The mechanism was found to involve direct regulation of Nrf2's
transactivation properties. Overall these results advance our knowledge of the
molecular mechanism(s) associated with the control of endogenous antioxidant
defences by physiological signals.